Methods of preparing pharmaceutical products adapted for injection into the human body



Patented Apr. 26, 1938 UNITED STATES METHODS OF PREPARING PHARMACEUTI-CAL PRODUCTS ADAPTED FOR INJECTION INTO THE HUMAN BODY Philip A. Kober,Evanston, 111., assignor to G. D.

Searle & 00., Chicago, Ill., a corporation or Illinois No Drawing.Application April 2'1, 1936, Serial No.- 76,701

12 Claims.

This invention relates to methods of preparing,

pharmaceutical products, and more particularly to processes for theproduction of medicinal agents in the nature of irritants adapted forintroduction, as by injection, into various regions of the human bodyfor the purpose of correcting structural abnormalities through theproduction of changes in the tissues involved or in contiguous tissues.

Pharmaceutical preparations of this general character have been knownand used for some time past in the treatment of various physicaldefects. For example, they have been injected into, and into theneighborhood of hernia] defects for the purpose of closing the defectsand strengthening contiguous structures by producing or stimulatingproliferation of connective and/or fibrous tissue. Such injections setup a mild tissue irritation in the margins of the ring or canal throughwhich the hernia protrudes and thus cause these tissues to throw outyoung fibrous tissue cells orfibro blasts which mature into tough adultfibrous tissue and ultimately close or obliterate the ring orcanal,thereby prohibiting the protrusion of the hernia. These medicinal agentsare also commonly used for the obliteration of varicose veins byinjecting them into the lumen of the veins and thereby producing aninflammatory reaction resulting in occlusion of the vessel lumen. forthe obliteration of hemorrhoids and of naevi by sclerosis of thevascular structures thereof, and for the shrinkage or obliteration ofcavities such as hydrocele sacs, bursae, and various types of cysts, aswell as soft tissue sinuses.

Among the different agents which have been used for these purposes arephenol, alcohol, zinc sulphate, glucose,. strong sodium chloridesolution, tannic acid and extracts containing tannins, urea, quinine,irritating resins and extracts containing them, and irritating mineralacids. Probably the most innocuous agents have been the salts or soapsof the fatty acids of various well known oils, particularly cod liveroil and castor oil. However, all of the substances heretofore studiedpossess the common serious disadvantage that the reparativeorproliferative process brought about by their injection is secondary toan exudative reaction which is sometimes accompanied by necrosis andeven abscess formation. These agents first exert upon the tissueinjected a severe irritating action which causes the tissue to throw outa serous exudate or an accumulation of serum containing a large numberof polymorphonuclear cells, and repair comes only as a secondaryreaction to the initial tissue destruction. Another disadvantageoi thepreparations previously known resides in the fact that these agents arein general harmful if introduced into the blood stream, a result whichis not unlikely to occur accidentally during their use. For example, itis known that certain of these agents, particularly the soaps made fromcastor oil and cod liver oil, are hemolytic in character and that theirintroduction into the circulation is therefore undesirable. It is alsoknown that the acids of castor oil are pharmacologically active andthattheir effects may be deleterious should they find their way into thegeneral circulation. Still another disadvantage of the hernial solutionspreviously used is that serious complications may'reault from theirinjection into the peritoneal cavity orinto the hernial sac.

It is therefore one of the objects or the present invention to provide amethod capable of producing a pharmaceutical preparation particularlyadapted for use in the injection treatment oi structural abnormalitiesof the human body which will be both highly effective in its intendedaction and also free of the disadvantages of the various agents hithertoknown and used for similar purposes.

Another object is to provide an efiective method for making apharmaceutical product of novel composition which maybe safely injectedinto the human body without danger of harmful reaction and which willserve in a remarkably efiective manner as a means of stimulating, therepair of body abnormalities of the types previously mentioned.

A further object is to provide a novel method for preparing a medicinalagent i of new and, unusual character which is especially well adaptedfor use in the injection treatment of hernia.

Still another object is to provide .a method whereby a new product ofthe character described may be easily and economically prepared fromreadily obtainable materials.

These and other objects will appear more fully upon a consideration ofthe detailed description of the preferred embodiment of the inventionwhich follows.

It has been discovered that a pharmaceutical product of the charactersought, possessing unusually desirable features and free from thevarious disadvantages of the preparations previously known and used forsimilar purposes, can be produced in a novel and practical manner fromthe oil of various seeds of the Plantago family, es-

. pecially the blond psyllium seeds known as Plantago ovate or Plantagoispaghula. By setting free the fatty acids of this oil, purifying them,and then causing them to combine with an inorganic or organic basicingredient to form salts or soaps of the acid and the basic ingredient,a product is obtained which, as has been thoroughly demonstrated byclinical tests, is particularly well adapted for the repair of thoseabnormalities of the human body which are treated by injecting into thebody medicinal agents in the nature of irritants which serve asproliferative stimulants for connective and fibrous tissue, or asobliterative and sclerosing agents for vascular tissue. Although theexact chemical composition of this new product cannot be stated withcertainty, it has been determined that its effectiveness as apharmaceutical agent for the injection treatment of these variousphysical conditions is due to the presence therein of the salts or soapsof the fatty acids of the oil derived froin psyllium seeds.

In preparing this product, the oil is preferably obtained fromthe'psyllium seeds by grinding and milling and then extracting the oilwith suitable fat solvents in any desired manner. The oil may also beobtained from parts of the milled seeds such as the hulls which are anarticle of commerce. After clarification the oil is saponified with analcoholic alkali in the customary manner to produce salts of the fattyacids of the oil. These salts are then acidified, as with hydrochloricacid. Upon acidification the fatty acids are liberated in the form of anoily layer and, being insoluble in water, may be readilycollected andpurified by washing with water. The purified fatty acids are nextconverted to water soluble salts or soaps by combination with aninorganic basic ingredient such as sodium, potassium, or ammoniumhydroxides, or with an organic basic ingredient such as triethanolamineor methylamine. The salts may be treated with organic solvents tofurther remove impurities. The resultant purified salts or soaps arepreferably prepared for commercial use in the form of aqueous solutionswhich may, if desired, also include a small amount of some antiseptic oranaesthetic such as benzyl alcohol. The final solution is usuallyfiltered with animal charcoal before being bottled.

Although it will be recognized by those skilled in the art that thespecific steps of the method of the present invention may be varied incertain respects, the following procedure has been found preferable inthe practice of the invention. 1200 grams of psyllium seed oil areplaced in suspension in 2750 cc. of ethyl alcohol and the mixture isheated in a water bath until the internal temperature is about 50 0.During this operation, it is probable that some of the oil is dissolved.The psyllium seed oil used may be obtained in any suitable manner, as byextraction with fat solvents from milled psyllium seed hulls aspreviously mentioned. 325 cc. of a cold 50% solution (by weight) ofsodium hydroxide are then poured slowly into the heated oil and alcoholwhile the same is stirred. The resulting mixture is permitted to standwith occasional shaking for approximately fifteen minutes, at the end ofwhich time distilled water is added until the total volume equals 6liters. The soap solution thus produced is then poured into a solutionof 2000 cc. of distilled water and 600 cc. of concentrated hydrochloricacid, accompanied by vigorous stirring. As a result of theacidification, the fatty acids which are insoluble in water rise to thesurface and may be readily siphoned of! from the aqueous layer. Thefatty acids are then washed with 5 liters of hot distilled water,separated from the washing water, and filtered to remove impurities. 700grams of the fatty acids thus obtained and 300 grams of benzyl alcoholare then placed in suspension in 13,000 cc. of distilled water, afterwhich a 10% solution (by weight) of sodium hydroxide is added slowly,accompanied by stirring, until the pH of the resulting solution is 8.3as determined with phenolphthalein as indicator. The solution thusproduced is then diluted with distilled water to a volume of 15,000 cc.and finally filtered with animal charcoal to remove any remainingimpurities. This final solution, which may be characterized as anapproximately 5% aqueous solution of the sodium salts of the fatty acidsof an oil of the type obtained from psyllium seeds, is then bottled insterile containers or otherwise suitably prepared for marketing.

There is thus provided by the present invention a novel and usefulmethod for the preparation of a pharmaceutical product which isparticularly well adapted for the treatment of various abnormalities ofthe human body. The product of this method is different from andsuperior to those hitherto known and used for similar purposes in thatit can be injected intravenously in massive doses without harm, ascontrasted with the dangers attending intravenous injection of causticor escharotic agents, tannins, resins, or metallic salts such as zincsulphate. Consequently, accidental escape from the site of injectioninto the general circulation of the body cannot cause serious injury asoften results when these other agents are used. It has also been foundthat the preparation produced by the method of the present invention isless prone to cause hemolysis than are salts prepared from the acids ofother oils such as castor oil or cod liver oil, and hence is less likelyto cause harm should some of the injected solution find its way into theblood stream. Another of the more important distinctions between theproduct of the present process and those of the prior art resides in thefact that injection into the body of a solution containing salts of thefatty acids of psyllium seed oil produces a primary proliferation andrapid maturation of connective tissue, whereas the injection ofpreviously known agents produces first an exudative reaction accompaniedby tissue necrosis, the proliferation of tissue coming only as asecondary reaction to the primary destruction caused by the injectedagent. Clinical tests of this product on human beings have proven thatit is highly effective in its action, that it can be freely used withoutserious ill effects, and that its use causes little or no pain to thepatient. These and other advantages of the product, together with thesimplicity, ease and economy of the procedure by which it is made, areindicative of the novelty, usefulness and practical importance of themethod herein disclosed.

Although only one specific embodiment of the method of the presentinvention has been described in detail, it will be understood that theinvention is not limited to the precise procedure described, but iscapable of variation in a number of respects. For example, although ithas been found preferable to utilize as the starting material the oilextracted from blond psyllium seeds, the oils obtained from variousother seeds of the Plantago family may also be used. It is alsocontemplated that an oil possessing the same characteristics as psylliumseed oil may be produced synthetically or artificially and used insteadof the natural oil. Furthermore, while in its preferred form the productof the present method comprises an approximately 5% aqueous solution ofthe sodium salts of the fatty acids of psyllium seed oil containing asmall amount of be'nzyl alcohol as an anaesthetic, it will be obvious tothose skilled in the art that other salts or soaps of the acids may beused, that the benzyl alcohol may be either omitted or replaced by otheranaesthetics or antiseptics, and that the concentration of the solutionmay be varied as desired within those limits which are satisfactory tothe medical profession. Moreover, the specifically disclosed product ofthe method of the present invention, which is thesubject matter ofapplication, Serial No. 76,702, filed April .27, 1936, is not to beconsidered as limitative of the scope of the invention represented bythe method. Reference is therefore to be had to the appended claims fora definition of the limits of the invention.

What is claimed is:

1. A method of preparing a pharmaceutical product adapted for injectioninto the human body including the steps of forming an aqueous suspensionof the fatty acids of the oil obtained from psyllium seeds, and thenconverting said acids to water soluble salts by adding to the suspensiona soluble basic ingredient.

2. A method of preparing a pharmaceutical product adapted for injectioninto the human body including the steps of forming an aqueous suspensionof the fatty acids of the oil obtainedfrom psyllium seeds, andthenconverting said acids to their sodium salts by adding to thesuspension a dilute solution of sodium hydroxide.

3. A method of preparing a pharmaceutical product adapted for injectioninto the human body including the steps of forming an aqueous suspensionof the fatty acids obtained from psyllium seed oil, and thenneutralizing said acids by adding to the suspension a solubleorganic orinorganic basic ingredient until the pH of the resulting solution isapproximately 8.3.

4. A method of preparing a pharmaceutical product adapted for injectioninto the human body including the steps of forming a suspension of thefatty acids obtained from psyllium seed oil and benzyl alcohol inwater,'and then neutralizing said acids by adding to the suspensionsodium hydroxide in such amount as to bring the pH of the resultingsolution to approximately 8.3.

5. A'method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of saponifying the oil obtainedfrom psyllium seeds, liberating the fatty acids of said saponified oilby acidification, and

' then converting said acids'into soluble salts.

6. A method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of saponifying the oil obtainedfrom psyllium seeds, liberating the fatty acids of said saponified oilby acidification,

, collecting and purifying the fatty acids thus obtained, and thenconverting said acids into solubie salts.

7. A method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of saponifying the oil obtainedfrom psyllium seeds, liberating the fatty acids of said saponified oilby acidification, collecting and purifying the fatty acids thusobtained, and then converting said acids into their sodium salts.

8. A method of preparing a pharmaceutical product adapted for injectioninto the human saponified oil by acidification, forming an aqueoussuspension of said fatty acids, and then neutralizing said acids byadding to the suspension sodium hydroxide in such amount as to bring thepH of the resulting solution to approximately 8.3.

10. A method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of extracting from psylliumseed hulls the oil contained therein, mixing said oil with alcohol andheating said mixture, saponifying said oil by adding to said mixture analkaline solution, acidifying the resulting soap solution and collectingthe fatty acids thus produced, forming an aqueous suspension of saidfatty acids, and then converting said acids to soluble salts by addingto the suspension a soluble basic ingredient.

11. A method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of extracting from psylliumseed hulls the oil contained therein, mixing said oil with ethyl alcoholand heating said mixture, saponifying said oil by adding to said mixture9. cold alkaline solution, acidifying the resulting soap solution andcollecting the fatty acids thu's produced, suspending approximately 'l00grams of said acids and 300 grams of benzyl alcohol in about 13,000 cc.of distilled water, and then adding to the suspension sodium hydroxidesolution until the pH of the resulting solution is approximately 8.3.

12. A method of preparing a pharmaceutical product adapted for injectioninto the human body comprising the steps of extracting from psylliumseed hulls the oil contained therein, mixing said oil with ethyl alcoholand heating said mixture, saponifying said oil by adding'to said mixturea cold alkaline solution, acidifying the resulting soap solution andcollecting the fatty acids thus produced, suspending approximately 700grams of said acids and 300 grams of benzyl alcohol in about 13,000 cc.of distilled water, adding to the suspension sodium hydroxide solutionuntil the pH of the resulting solution is approximately 8.3, dilutingthe resulting solution with distilled water to avolume of about 15.000cc., and removing the undesired impurities therefrom.

PHILIP A. KOBER.

